Obesity endangers the lives of millions of people worldwide, through comorbidities such as heart disease, cancers, type 2 diabetes, stroke, arthritis, and major depression. At this time, available non-surgical treatments for obesity, including drugs, are palliative and effective only while treatment is maintained. When treatments are discontinued, weight gain inevitably results. For obesity treatments to work, they must affect energy intake, absorption, expenditure or storage. While many drugs have been marketed or are currently under investigation for the treatment of obesity, several have adverse side effects, including insomnia, asthenia, fecal incontinence, hypertension, tachychardia, valvular heart abnormalities, and even death. Accordingly, several weight loss drugs have been banned by the Food and Drug Administration, including the first one approved for this indication, desoxyephedrine (1946), and more recently d-fenfluramine/fenfluramine (September, 1997) and ephedrine alkaloids (April, 2004).
Research over the past fifteen years has revolutionized the understanding of molecular mechanisms that homeostatically control body weight and fat. Accumulated findings support a lipostatic hypothesis of energy homeostasis, in which the brain seeks to retain stored energy constant over long periods as adipose tissue. Accordingly, a highly integrated, redundant neurohumoral energy homeostasis feedback system, through behavioral and metabolic mechanisms, serves to minimize the impact of short-term fluctuations in energy balance, and especially negative energy balance, on fat mass. The identification of genes whose loss of function mutations result in monogenic obesity syndromes or confer resistance to obesity in humans or rodents have provided critical genetic entry points for characterizing the interconnected pathways that regulate energy homeostasis. The identification of these receptors and ligands has led to research efforts to target signals at both ends of the energy spectrum, however, no vaccine or treatment modality based on these research efforts is currently available for treating obese patients.